A novel and facile synthesis of 3 (2 benzofuroyl) and 3,6 bis(2 benzofuroyl)carbazole derivatives 1533 A novel and facile synthesis of 3 (2 benzofuroyl) and 3,6 bis(2 benzofuroyl)carbazole derivatives[.]
A novel and facile synthesis of 3-(2-benzofuroyl)- and 3,6-bis(2-benzofuroyl)carbazole derivatives Wentao Gao*, Meiru Zheng and Yang Li Full Research Paper Address: Institute of Superfine Chemicals, Bohai University, Jinzhou 121000, China Open Access Beilstein J Org Chem 2011, 7, 1533–1540 doi:10.3762/bjoc.7.180 Email: Wentao Gao* - bhuzh@163.com Received: 21 July 2011 Accepted: 26 October 2011 Published: 17 November 2011 * Corresponding author Associate Editor: J A Porco Jr Keywords: 2-benzofuroyl; carbazole; PEG-400; Rap–Stoermer reaction; salicylaldehydes; ultrasound-assisted © 2011 Gao et al; licensee Beilstein-Institut License and terms: see end of document Abstract A facile synthesis of hitherto unreported 3-(2-benzofuroyl)carbazoles 3a–k, 3,6-bis(2-benzofuroyl)carbazoles 5a–k, and naphtho[2,1-b]furoylcarbazoles 3l and 5l is described The synthesis mainly relies on the ultrasound-assisted Rap–Stoermer reaction of 3-chloroacetyl- (1) or 3,6-dichloroacetyl-9-ethyl-9H-carbazole (4) with various salicylaldehydes 2a–k as well as 2-hydroxy1-naphthaldehyde (2l) in CH3CN with the presence of PEG-400 as catalyst The procedure offers easy access to benzofuroylcarbazoles in short reaction times and the products are obtained in moderate to good yields Introduction Carbazole, and especially heterocycle-containing carbazole derivatives, are embodied in many naturally occurring products [1-3] and display a broad spectrum of useful biological activities such as antitumor, antimitotic, and antioxidative activities [4-6] They are also widely used as building blocks for new organic materials [7-10], and play a very important role in electroactive and photoactive devices [11-14] Therefore, a number of methodologies for the construction of heterocycle-containing carbazoles have been reported in recent years [15-19] Most heterocycle-containing carbazoles reported in the literature comprise a common heterocyclic ring moiety fused with a carbazole ring, such as pyridocarbazoles [20,21], thienocarbazoles [22,23], pyranocarbazoles, pyrrolocarbazoles [24,25], indolocarbazoles [26-28], and synthetic analogues thereof However, there are very few reports in which the heterocyclic moiety is substituted with a carbazole unit Hence the synthesis of such compounds is desirable [29,30] On the other hand, the benzofuran derivatives are an important class of heterocyclic compounds that are known to possess important biological properties [31-33] Especially, recent studies have shown that some benzofuroyl-based compounds display important biological properties as antimicrobial [34], anticonvulsant, anti-inflammatory [35], anti-tumor [36], and antifungal [37,38] activities On account of these findings, extensive synthetic efforts have been devoted to the development of more novel and interesting benzofuroyl-based compounds [39-43] 1533 Beilstein J Org Chem 2011, 7, 1533–1540 We have recently reported the synthesis of quinolyl-substituted carbazoles [44] and benzofuranyl-substituted quinoline [45] Thus, in light of the above findings and in the context of our ongoing work on the synthesis of new heterocyclic compounds, we found it an attractive idea to construct new prototypes combining both the carbazole ring system and benzofuran framework in the same molecule Such compounds are not only synthetically challenging but may also be vitally important for pharmacological studies or in the realization of new medicinal properties Therefore, we report herein the synthesis of a series of novel 3-(2-benzofuroyl)carbazoles and 3,6-bis(2-benzofuroyl)carbazoles ture of the resulting products, from which we could not separate any desired products in appreciable yields After many trials, we found that when the Rap–Stoermer reaction was carried out with PEG-400 (0.5 equiv) as catalyst in the presence of K CO as base in refluxing CH CN for 10 h, the desired benzofurans 3a were obtained, but the attempt was still plagued by low yield In this reaction the use of 0.5 equivalents of PEG-400 was found most suitable with and 2a to provide a maximum yield of 3a of only 29% There was no further improvement in the yields upon increasing the amount of catalyst or the reaction time As a result, attempts to find an alternative approach are still very desirable Results and Discussion Recently, the ultrasound technique has increasingly been used in synthetic organic chemistry A large number of organic reactions can be carried out with a higher yield, in shorter reaction time and under milder conditions with the aid of ultrasonication For example, Palimkar et al [52] ever reported a facile ultrasound-promoted synthesis of benzo[b]furan derivatives Accordingly, the versatility of the ultrasound technique prompted us to further experiment with this approach Interestingly, we found that when the same reaction as above was adopted in conjunction with ultrasonic irradiation, an improvement in terms of yield (72%) and reaction time (3 h) was achieved In addition, we also observed that if the ultrasoundassisted Rap–Stoermer reaction was performed in the absence of PEG-400, the desired products were not obtained in appreciable yields, which indicates that both the catalysis by PEG-400 and the ultrasonication together promoted this reaction To establish the generality and applicability of this method, a wide variety of salicylaldehydes were subjected to the same set of conditions to furnish the corresponding 3-(2benzofuroyl)carbazole derivatives It was found that all the salicylaldehydes partners worked well The reactions were generally complete within h and the corresponding 3-(2benzofuroyl)carbazole derivatives 3a–l were produced in good yields of 60–72%, as shown in Table In order to synthesize the targeted compounds through a facile and direct methodology, we devised a route that made use of the Rap–Stoermer reaction [46], and which could provide opportunity for the direct construction of 2-benzofuroyl-based compounds through base-mediated reaction of salicylaldehydes with α-haloketones The synthetic route developed in our laboratory for the preparation of 3-(2-benzofuroyl)carbazoles 3a–k by the Rap–Stoermer reaction of 3-chloroacetyl-9-ethyl-9H-carbazole (1) with a variety of salicylaldehydes 2a–k is summarized in Scheme The Rap–Stoermer reaction was normally performed in alcoholic medium but often produced poor to moderate yields of benzofuran products [47,48] Considering this fact, we conducted our own initial investigation towards the synthesis of 3a according to reported methods under solvent-free [49] or solvent-free, microwave-irradiation conditions [50] Unfortunately, it was found that the Rap–Stoermer reaction did not occur or gave intractable, complex mixtures (as observed by TLC), according to both methods More recently, Shang et al [51] described the base-mediated 4-dimethylaminopyridine (DMAP)-catalyzed Rap–Stoermer reaction for the synthesis of 2-benzofuroyl compounds in good yields between salicylaldehydes and halogenated ketones in water Although the methodology is elegant and impressive, our attempts to follow the route to synthesize 3a were also frustrated by the very complex mix- The results summarized in Table indicated the scope and generality of the PEG-400-catalyzed, ultrasound-assisted Scheme 1: PEG-400 catalyzed ultrasound-assisted Rap–Stoermer synthesis of 3-(2-benzofuroyl)carbazoles 3a–k 1534 Beilstein J Org Chem 2011, 7, 1533–1540 Table 1: Synthesis of 3-(2-benzofuroyl)carbazole derivatives (3a–k) Entry Compound Yield (%)a mp (°C) 3a 72 102–103 3b 68 157–159 3c 62 144–145 3d 63 120–122 3e 66 129–130 3f 65 135–136 3g 67 119–120 3h 69 228–230 1535 Beilstein J Org Chem 2011, 7, 1533–1540 Table 1: Synthesis of 3-(2-benzofuroyl)carbazole derivatives (3a–k) (continued) 3i 62